In the hemocatharsis for therapy of renal failure, etc., modules such as hemodialyzers, hemofilters and hemodiafilters, which comprise dialysis membranes or ultrafilter membranes as separators, are widely used in order to remove urinal toxic substances and waste products in blood. Dialysis membranes and ultrafilter membranes as separators are made of natural materials such as cellulose or the derivatives thereof (e.g., cellulose diacetate, cellulose triacetate, etc.) or synthetic polymers such as polysulfone, polymethyl methacrylate, polyacrylonitrile, etc. The importance of modules comprising the hollow fiber membranes as separators is very high in the field of dialyzers, in view of the advantages such as the reduction of the amount of extracorporeal circulated blood, high efficiency of removing undesired substances in blood, and high productivity of manufacturing modules.
Highly water permeable polysulfone-based resins have attracted public attentions, because such resins are most suitable for the advanced dialysis technology, among the above-listed membrane materials. However, semipermeable membranes made of a polysulfone-based resin alone are poor in affinity with blood, inducing airlock phenomena, since the polysulfone-based resin is hydrophobic. Therefore, such semipermeable membranes as they are can not be directly used for treating blood.
To solve this problem, there is proposed a method for imparting hydrophilicity to a membrane by blending a polysulfone-based resin with a hydrophilic polymer: for example, a polyhydric alcohol such as polyethylene glycol or the like is added to a polysulfone-based resin (cf. Patent Literature 1 and Patent Literature 2);
or otherwise, polyvinyl pyrrolidone is added to a polysulfone-based resin (cf. Patent Literature 3 and Patent Literature 4).
These methods are effective to solve the above-discussed problem. However, searching of the optimum conditions for the hydrophilicity-imparting technique by blending a hydrophilic polymer is very important, because the concentration of the hydrophilic polymer in the inner surface of a hollow fiber membrane on the blood-contacting side and the concentration of the hydrophilic polymer in the outer surface thereof give significant influence on the capacities of the hollow fiber membrane. For example, the compatibility of a hollow fiber membrane with blood can be reliably obtained by increasing the concentration of a hydrophilic polymer in the inner surface of the membrane, while too high a concentration of the hydrophilic polymer in the inner surface of the membrane increases the amount of the hydrophilic polymer eluted into blood. Undesirably, the accumulation of the eluted hydrophilic polymer over a long period of dialysis therapy induces side effects or complications.
On the other hand, too high a concentration of the hydrophilic polymer in the outer surface of the membrane deteriorates the endotoxin-adsorbing performance and induces a possibility of the infiltration of endotoxin in a dialyzate into the blood side. As a result, side effects such as fever, etc. are induced, or the hydrophilic polymer in the outer surfaces of the hollow fiber membranes permits the sticking of such membranes to one another while the membranes are being dried, which results in a new problem that the incorporation of such membranes into a module becomes difficult.
On the contrary, a lower concentration of the hydrophilic polymer in the outer surface of the hollow fiber membrane is preferable, since the infiltration of endotoxin into the blood side can be suppressed. However, the hydrophilicity of the outer surface of the hollow fiber membrane becomes lower, which causes a problem in that the outer surface of the hollow fiber membrane becomes poor in compatibility with a physiological saline for use in wetting the membrane, when a bundle of dried hollow fiber membranes is wetted and incorporated into a module. As a result, undesirably, the priming of the membranes (purging the membranes of an air when wetting the same) becomes lower in efficiency.
There is disclosed a method for solving these problems (cf. Patent Literature 5): that is, the concentration of a hydrophilic polymer in the dense layer of the inner surface of a hollow fiber membrane is adjusted within a specified range, and the content of the hydrophilic polymer in the dense layer of the inner surface of the membrane is at least 1.1 times larger than the content of the hydrophilic polymer in the outer surface of the membrane. In particular, this method is based on a technical idea to increase the content of the hydrophilic polymer in the dense layer of the inner surface of the membrane to thereby improve the compatibility thereof with blood, and to decrease the content of the hydrophilic polymer in the outer surface of the membrane to thereby suppress the sticking of the hollow fiber membranes which would occur when drying the membranes. This technique solves one of the problems: i.e., the infiltration of endotoxin in a dialyzate into the blood side is inhibited. However, there still remains unsolved the problem that the priming of the membrane tends to lower because of too low a content of the hydrophilic polymer in the outer surface of the membrane. It is therefore needed to solve this problem.
There is disclosed another method of solving the problem of the infiltration of endotoxin in a dialyzate into the blood side (cf. Patent Literature 6). In this method, the contents of hydrophilic polymers in the proximate layer of the inner surface and the outer surface, and the intermediate layer of a hollow fiber membrane having an uniform membrane structure are specified so as to suppress the infiltration of endotoxin into the blood side. However, also, this method can not solve the problem of lower priming of the membrane, like the former method. In addition, there is a further problem in that the larger size pores of the outer surface of the hollow fiber membrane lower the pressure resistance of the membrane. Therefore, such a membrane has a possibility of bursting when used for hemodiafiltration or the like in which the pressure of a fluid is higher than that for the conventional therapies.
There are further disclosed methods for improving the compatibility of membranes with blood and for reducing the amount of hydrophilic polymers eluted into blood, by specifying the contents of the hydrophilic polymers in the inner surfaces of hollow fiber membranes (cf. Patent Literature 7 to Patent Literature 9).
However, any of the above patent literature does not teach the content of the hydrophilic polymer present in the outer surface of the hollow fiber membrane, and thus, any of the inventions of the above publications is not able to improve all the problems attributed to the content of the hydrophilic polymer present in the outer surface of the hollow fiber membrane.
There is disclosed a method of solving the problem of the infiltration of endotoxin into the blood side, out of the above-discussed problems (cf. Patent Literature 10). This method is devised by taking advantage of the properties of endotoxin which has a hydrophobic moiety in the molecule and which is apt to be adsorbed onto a hydrophobic material. Specifically, in this method, the ratio of a hydrophilic polymer to a hydrophobic polymer in the outer surface of a hollow fiber membrane is adjusted to 5 to 25%. Surely, this method is effective to suppress the infiltration of endotoxin into the side of blood. However, it is needed to remove the hydrophilic polymer in the outer surface of the membrane by washing, so as to impart this feature to the membrane. Accordingly, long treating time is required for this washing, which is disadvantageous in cost. For example, in an Example of the invention of the above patent publication, a hollow fiber membrane is washed by showering with hot water of 60° C. for one hour and washed with hot water of 110° C. for one hour.
This method of decreasing the amount of the hydrophilic polymer in the outer surface of the membrane is effective to inhibit the infiltration of endotoxin into the side of blood. However, the hydrophilicity of the outer surface of the membrane becomes lower, which causes the following disadvantage: when a bundle of hollow fiber membranes dried to be incorporated into a module is again wetted, the hollow fiber membranes are poor in compatibility with physiological saline for wetting the membranes. Undesirably, this method may induce poor priming, i.e., insufficient purging the membranes of an air in the membrane-wetting step. For example, there are disclosed methods of improving this problem, in which a hydrophilic compound such as glyceline or the like is blended (cf. Patent Literature 11 and Paten Literature 12). These methods, however, have problems in that the hydrophilic compound behaves as a foreign matter during dialysis and also tends to deteriorate by light or the like, which gives an adverse influence on the storage stability of a module, and also in that the hydrophilic compound hinders an adhesive from bonding for fixing a bundle of hollow fiber membranes in a module when the membranes are incorporated into the module.
There are disclosed methods of avoiding the sticking of hollow fiber membranes, i.e., another problem out of the foregoing problems: in any of these methods, the ratio of pore areas of the outer surface of a membrane is adjusted to 25% or more (cf. Patent Literature 6 and Patent Literature 13). While these methods are surely effective to prevent the sticking of the hollow fiber membranes, the strength of the membranes becomes lower due to the higher ratio of pore areas, which may lead to the leakage of blood or the like.
Further, a method by specifying the ratio of pore areas and the pore area of the outer surface of a membrane is disclosed (cf. Patent Literature 14).
In the meantime, when a module packed with hollow fiber membranes is used as a medical device, sterilization thereof is indispensable. While the sterilization methods such as sterilization using an ethylene oxide gas or a compressed vapor are conventionally employed, recently, sterilization methods by exposure to radioactive rays have come into wide use, because the exposure to radioactive rays are high in sterilization effect and makes it possible to sterilize a subject matter enveloped in a package with ease. However, the sterilization by way of exposure to radioactive rays brings about decomposed substances from hollow fiber membranes and potting materials, and elution of such decomposed substances may induce side effects in clinical use. There is known a membrane filled with water and sterilized by exposure to a γ-ray, which exhibits high water permeability and which is crosslinked to inhibit the elution of a hydrophilic polymer therefrom. However, this membrane is heavy because of the water filling the same, and thus is poor in handling ease.
To solve this problem, there is disclosed a method for sterilization by exposure to a radioactive ray without using water (cf. Patent Literature 15). In this method, a hollow fiber membrane, adjusted in the oxygen concentration to 0.1 to 3.6% and adjusted in the moisture content to at least 4%, is exposed to a radioactive ray. According to this method, a hollow fiber membrane is evaluated as being low in elution and high in safety, when the amount of consumed aqueous potassium permanganate solution is less than a given value. However, the sterilization of a hollow fiber membrane having a relatively high oxygen concentration of 0.1 to 3.6% by way of exposure to a radioactive ray has a possibility of exciting oxygen radicals under the exposure to the radioactive ray, followed by acceleration of the oxidative decomposition of the materials due to the excited oxygen radicals, which particularly may lead to poor storage stability.
Patent Literature 1: JP-A-61-232860
Patent Literature 2: JP-A-58-114702
Patent Literature 3: JP-B-5-54373
Patent Literature 4: JP-B-6-75667
Patent Literature 5: JP-A-6-165926
Patent Literature 6: JP-A-2001-38170
Patent Literature 7: JP-A-6-296686
Patent Literature 8: JP-A-11-309355
Patent Literature 9: JP-A-2000-157852
Patent Literature 10: JP-A-2000-254222
Patent Literature 11: JP-A-2001-190934
Patent Literature 12: U.S. Pat. No. 3,193,262
Patent Literature 13: JP-A-7-289863
Patent Literature 14: JP-A-2000-140589
Patent Literature 15: JP-A-2003-245526